EP2282991B1 - Method for the production of 1,4-benzothiepin-1,1-dioxide derivatives - Google Patents
Method for the production of 1,4-benzothiepin-1,1-dioxide derivatives Download PDFInfo
- Publication number
- EP2282991B1 EP2282991B1 EP09737876.4A EP09737876A EP2282991B1 EP 2282991 B1 EP2282991 B1 EP 2282991B1 EP 09737876 A EP09737876 A EP 09737876A EP 2282991 B1 EP2282991 B1 EP 2282991B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- alkyl
- production
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims description 66
- 238000004519 manufacturing process Methods 0.000 title claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 232
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 153
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 105
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 85
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 83
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 49
- 239000002904 solvent Substances 0.000 claims description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 238000010626 work up procedure Methods 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 15
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 239000011877 solvent mixture Substances 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 12
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 7
- 229940126657 Compound 17 Drugs 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- -1 2,2,6,6-tetramethylpiperidinyloxyl Chemical group 0.000 claims description 6
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 229910015900 BF3 Inorganic materials 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- NMVXHZSPDTXJSJ-UHFFFAOYSA-L 2-methylpropylaluminum(2+);dichloride Chemical compound CC(C)C[Al](Cl)Cl NMVXHZSPDTXJSJ-UHFFFAOYSA-L 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- YXMVRBZGTJFMLH-UHFFFAOYSA-N butylsilane Chemical compound CCCC[SiH3] YXMVRBZGTJFMLH-UHFFFAOYSA-N 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 3
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 229940125758 compound 15 Drugs 0.000 claims description 2
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 229960001922 sodium perborate Drugs 0.000 claims description 2
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 4
- QXYJCZRRLLQGCR-UHFFFAOYSA-N dioxomolybdenum Chemical compound O=[Mo]=O QXYJCZRRLLQGCR-UHFFFAOYSA-N 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 1
- 229910006069 SO3H Inorganic materials 0.000 claims 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims 1
- 229940125797 compound 12 Drugs 0.000 claims 1
- 229940125877 compound 31 Drugs 0.000 claims 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 238000006243 chemical reaction Methods 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 19
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- 230000035484 reaction time Effects 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- ZNOVTXRBGFNYRX-UHFFFAOYSA-N 2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-UHFFFAOYSA-N 0.000 description 11
- 229960004592 isopropanol Drugs 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000012071 phase Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 0 C*[C@](C)([C@](C)(*)[C@]1(C)*)[C@@](C)(*)O[C@]1*=[N+][O-] Chemical compound C*[C@](C)([C@](C)(*)[C@]1(C)*)[C@@](C)(*)O[C@]1*=[N+][O-] 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000003863 ammonium salts Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- 238000005292 vacuum distillation Methods 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- WGABOZPQOOZAOI-UHFFFAOYSA-N 2-[4-[[(3,5-dimethoxy-4-methylbenzoyl)-(3-phenylpropyl)amino]methyl]phenyl]acetic acid Chemical compound COC1=C(C)C(OC)=CC(C(=O)N(CCCC=2C=CC=CC=2)CC=2C=CC(CC(O)=O)=CC=2)=C1 WGABOZPQOOZAOI-UHFFFAOYSA-N 0.000 description 2
- FBPINGSGHKXIQA-UHFFFAOYSA-N 2-amino-3-(2-carboxyethylsulfanyl)propanoic acid Chemical compound OC(=O)C(N)CSCCC(O)=O FBPINGSGHKXIQA-UHFFFAOYSA-N 0.000 description 2
- DSKYSDCYIODJPC-UHFFFAOYSA-N 2-butyl-2-ethylpropane-1,3-diol Chemical compound CCCCC(CC)(CO)CO DSKYSDCYIODJPC-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- NXTNASSYJUXJDV-UHFFFAOYSA-N 3-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(C(Cl)=O)=C1 NXTNASSYJUXJDV-UHFFFAOYSA-N 0.000 description 2
- UXBLSWOMIHTQPH-UHFFFAOYSA-N 4-acetamido-TEMPO Chemical compound CC(=O)NC1CC(C)(C)N([O])C(C)(C)C1 UXBLSWOMIHTQPH-UHFFFAOYSA-N 0.000 description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 2
- 241001136792 Alle Species 0.000 description 2
- 235000001258 Cinchona calisaya Nutrition 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
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- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
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- 229940125782 compound 2 Drugs 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
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- 150000003839 salts Chemical class 0.000 description 2
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- 238000003786 synthesis reaction Methods 0.000 description 2
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- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 1
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- DZJCBMUZHJJDHZ-RBQQCVMASA-N CC[C@@](CC=1CC)(CS=1(c(c(Cc1cccc([N+]([O-])=O)c1)c1)ccc1F)=O)C=O Chemical compound CC[C@@](CC=1CC)(CS=1(c(c(Cc1cccc([N+]([O-])=O)c1)c1)ccc1F)=O)C=O DZJCBMUZHJJDHZ-RBQQCVMASA-N 0.000 description 1
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- RRMBSCLWEMOVLK-LAUBAEHRSA-N CC[C@](C)(C[C@H](Cc1cc(N)ccc1)c1cc(F)ccc1C1)CS1(=O)=O Chemical compound CC[C@](C)(C[C@H](Cc1cc(N)ccc1)c1cc(F)ccc1C1)CS1(=O)=O RRMBSCLWEMOVLK-LAUBAEHRSA-N 0.000 description 1
- WUZBOJXXYMKMMF-UHFFFAOYSA-N COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F Chemical compound COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F WUZBOJXXYMKMMF-UHFFFAOYSA-N 0.000 description 1
- SHGYFQZQYWWVJI-ZJPYXAASSA-N CO[C@H]([C@@H](C[O](C)=C)OC1(CC1)[C@@H]1OC)[C@@H]1OCc1ccccc1 Chemical compound CO[C@H]([C@@H](C[O](C)=C)OC1(CC1)[C@@H]1OC)[C@@H]1OCc1ccccc1 SHGYFQZQYWWVJI-ZJPYXAASSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229910019093 NaOCl Inorganic materials 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- CKBZMBPBJXHJTF-UHFFFAOYSA-N [O-][N+](c1cccc(C(c2cc(F)ccc2F)=O)c1)=O Chemical compound [O-][N+](c1cccc(C(c2cc(F)ccc2F)=O)c1)=O CKBZMBPBJXHJTF-UHFFFAOYSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- UQMRAFJOBWOFNS-UHFFFAOYSA-N butyl 2-(2,4-dichlorophenoxy)acetate Chemical compound CCCCOC(=O)COC1=CC=C(Cl)C=C1Cl UQMRAFJOBWOFNS-UHFFFAOYSA-N 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- ASLHVQCNFUOEEN-UHFFFAOYSA-N dioxomolybdenum;dihydrochloride Chemical compound Cl.Cl.O=[Mo]=O ASLHVQCNFUOEEN-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/19—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/19—Acids containing three or more carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
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- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
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- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
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- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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Definitions
- the invention relates to a process for the preparation of 1,4-benzothiepine-1,1-dioxide derivatives which are substituted by benzyl radicals.
- the stereocenters at positions 3, 4 and 5 of the thiepine system of the compound of the formula I should be optically pure or obtained.
- radicals or substituents can occur several times in the compounds of the formulas I, they may all independently of one another have the stated meaning and be identical or to be different.
- the star on a carbon atom in the compound of formula 10 / 10a means that the respective carbon atom is chiral and the compound is present either as an R or S enantiomer or as a mixture of the two enantiomers.
- the compound 10 or. 10a in enantiomerically pure form for example by reacting the compound of formula 8 with the compound of formula 5 under the reaction conditions indicated.
- the preparation of the compound of formula 10a succeeds analogously by reaction with the compound of formula 5a.
- the compound of formula 8 can be prepared, for example, by reacting the compound of formula 7 with 3-nitrobenzoyl chloride, in the presence of a suitable catalyst, such as, for example, aluminum (III) chloride.
- a suitable catalyst such as, for example, aluminum (III) chloride.
- the reaction temperature is from 40 ° C to 140 ° C, preferably from 80 ° C to 120 ° C.
- the reaction time is generally 2 to 24 hours, depending on the composition of the mixture and the selected temperature range.
- the resulting compound of formula 8 is then separated from the reaction mixture by aqueous work-up and extraction with a suitable solvent, for example ethyl acetate or dichloromethane, followed by crystallization.
- the compound of formula 1 can be prepared, for example, by reacting 2-butyl-2-ethyl-1,3-propanediol with suitable oxidizing agents, such as potassium permanganate.
- suitable oxidizing agents such as potassium permanganate.
- the reaction temperature is from 0 ° C to 100 ° C, preferably from 0 ° C to 40 ° C.
- the Reaction time is generally 2 to 8 hours, depending on the composition of the mixture and the selected temperature range.
- the resulting compound of formula 1 is then separated from the reaction mixture by aqueous work-up and extraction with a suitable solvent, for example ethyl acetate or dichloromethane.
- a purification can be carried out by means of a vacuum distillation.
- the compound of formula 1 can be obtained by the literature methods.
- the compound of formula 2a can be prepared, for example, by reacting racemic 2-butyl-2-ethyl-1,3-propanediol with chiral bases, such as quinine, in a suitable solvent or solvent mixture, such as toluene, n-butyl acetate or Acetone / water, reacted.
- chiral bases such as quinine
- a suitable solvent or solvent mixture such as toluene, n-butyl acetate or Acetone / water
- the reaction temperature of the racemate resolution is 0 ° C to 100 ° C, preferably from 20 ° C to 60 ° C.
- the reaction time is generally 2 to 24 hours, depending on the composition of the mixture and the selected temperature range.
- the obtained enantiomeric excesses (ee) are between 20 and 80% ee depending on the chosen conditions.
- ee values can be achieved when the resulting compound of formula 2a is subsequently recrystallized in a suitable solvent or solvent mixture such as toluene, n-butyl acetate / heptane or acetone / water.
- a suitable solvent or solvent mixture such as toluene, n-butyl acetate / heptane or acetone / water.
- the obtained enantiomeric excesses (ee) are between 80 and 99% ee, depending on the chosen conditions.
- the compound of formula 2 is then obtained by aqueous work-up and extraction with a suitable solvent, for example toluene, ethyl acetate or dichloromethane from the compound of formula 2a.
- a suitable solvent for example toluene, ethyl acetate or dichloromethane from the compound of formula 2a.
- compound 2 can be prepared by resolution with the compound of formula X2.
- the compound of formula 2 is then recovered from the compound of formula 2b by aqueous work-up and extraction with a suitable solvent, for example toluene, ethyl acetate or dichloromethane.
- a suitable solvent for example toluene, ethyl acetate or dichloromethane.
- the enantiomer (formula 2c) of compound 2 can be prepared by resolution with the antipode (formula X3) of compound X2.
- the compounds of formula 3 and 3a can be prepared, for example, by reacting the compound of formula 2 or 2c z. B. with hydrobromic acid without or with a suitable solvent or solvent mixture, such as toluene, reacted.
- the reaction temperature is 40 ° C to 120 ° C, preferably from 60 ° C to 100 ° C.
- the reaction time is generally 2 to 24 hours, depending on the composition of the mixture and the selected temperature range.
- the yields achieved are between 60 and 90%, depending on the chosen conditions.
- the preparation of the racemate succeeds analogously by passing the compound of formula 1 z. B. with hydrobromic acid analogously to the above conditions.
- the resulting compounds of the formula 3 and 3a or their mixture are then separated from the reaction mixture by aqueous workup and extraction with a suitable solvent, for example ethyl acetate or dichloromethane.
- a purification can be carried out by means of a vacuum distillation.
- the compounds of the formula 3 and 3a or mixtures thereof can be obtained by the literature methods.
- the compound of formula 3 or 3a can be obtained directly from the salts, such as 2a, 2b and 2d analogously to the conditions described.
- the compound of formula 5 can be prepared for example by reacting the bromide of the compound of formula 3 z. B. with potassium thioacetate in a suitable solvent or solvent mixture, such as toluene or acetone.
- a suitable solvent or solvent mixture such as toluene or acetone.
- the reaction temperature is from 0 ° C to 100 ° C, preferably from 20 ° C to 40 ° C.
- the reaction time is generally 2 to 24 hours, depending on the composition of the mixture and the selected temperature range.
- the resulting compounds of formula 4 are then separated from the reaction mixture by aqueous work-up and extraction with a suitable solvent, for example ethyl acetate or dichloromethane.
- the reaction product is not isolated, but directly in a suitable solvent or Solvent mixture, such as THF / toluene with a reducing agent such as.
- a suitable solvent or Solvent mixture such as THF / toluene with a reducing agent such as.
- LAH lithium aluminum hydride
- the reaction temperature is 0 ° C to 100 ° C, preferably 0 ° C to 40 ° C.
- a suitable solvent for example ethyl acetate, toluene or dichloromethane
- a purification can be carried out by means of a vacuum distillation.
- the resulting mixture of the compounds of formula 30 / 30a and 10 / 10a is completely converted by alkaline hydrolysis of the compound of formula 30 / 30a, for example with sodium methoxide in methanol or methanolic potassium hydroxide solution, in the compound of formula 10 / 10a and then by aqueous workup and extraction with a suitable solvent, for example toluene, ethyl acetate or dichloromethane separated from the reaction mixture.
- a suitable solvent for example toluene, ethyl acetate or dichloromethane
- the asterisk on a carbon atom in the compound of formula 10 means that the particular carbon atom is chiral and the compound is present either as an R or S enantiomer or as a mixture of the two enantiomers.
- the compound 10 or. 10a in enantiomerically pure form for example by reacting the compound of formula 8 with the compound of formula 35 under the reaction conditions indicated.
- the preparation of the compound of formula 10a succeeds analogously by reaction with the compound of formula 5a.
- the compound of formula 35 can be prepared for example by reacting the bromide of the compound of formula 3 z. B. with potassium thioacetate in a suitable solvent or solvent mixture, such as toluene or acetone.
- a suitable solvent or solvent mixture such as toluene or acetone.
- the reaction temperature is from 0 ° C to 100 ° C, preferably from 20 ° C to 40 ° C.
- the reaction time is generally 2 to 24 hours, depending on the composition of the mixture and the selected temperature range.
- the resulting compounds of formula 4 are then separated from the reaction mixture by aqueous work-up and extraction with a suitable solvent, for example ethyl acetate or dichloromethane.
- the reaction product is not isolated, but directly in a suitable solvent or Amsterdamsmittlegemisch, such as THF / toluene with a reducing agent such as. B. lithium aluminum hydride to the compound of formula 5 is reduced.
- the reaction temperature is 0 ° C to 100 ° C, preferably 0 ° C to 40 ° C.
- a suitable solvent for example ethyl acetate, toluene or dichloromethane
- the product is reacted with an acid chloride or acid anhydride under conditions known from the literature.
- the reaction mixture after reduction directly with an acid halide or carboxylic anhydride, such as.
- the reaction time is generally 1 to 4 hours, depending on the composition of the mixture and the selected temperature range.
- the resulting compound of formula 13 is then separated from the reaction mixture by aqueous workup and extraction with a suitable solvent, for example toluene, ethyl acetate, methyl tert-butyl ether or dichloromethane and crystallized.
- a suitable solvent for example toluene, ethyl acetate, methyl tert-butyl ether or dichloromethane and crystallized.
- the preparation of the compound of formula 13a succeeds analogously to the conditions mentioned for the compound of formula 13.
- the compound of formula 15 can be prepared, for example, by reacting the compound of formula 13 with a suitable base such as potassium carbonate, cesium carbonate, DBU, sodium or potassium ethylate or sodium or potassium tert-butylate, a suitable solvent such as 2 Propanol, toluene, THF, methyl THF or dimethoxyethane.
- a suitable base such as potassium carbonate, cesium carbonate, DBU, sodium or potassium ethylate or sodium or potassium tert-butylate
- a suitable solvent such as 2 Propanol, toluene, THF, methyl THF or dimethoxyethane.
- the reaction temperature is -70 ° C to 80 ° C, preferably from -20 ° C to 25 ° C.
- the resulting mixture of isomers can then be separated by chromatographic methods, such as chromatography on silica gel and toluene / ethyl acetate as the mobile phase, or fractional
- An embodiment of the invention further relates to individual reaction steps and intermediates of the process for preparing the compounds of the formulas 17, 17a, 17b and 17c.
- the compound of formula 16 can be prepared, for example, by reacting the compound of formula 15 with a suitable reducing agent such as hydrogen / palladium on charcoal in a suitable solvent such as methanol, ethanol, 2-propanol, dichloromethane, toluene, THF, Reacting methyl THF or dimethoxyethane.
- a suitable reducing agent such as hydrogen / palladium on charcoal
- a suitable solvent such as methanol, ethanol, 2-propanol, dichloromethane, toluene, THF, Reacting methyl THF or dimethoxyethane.
- the reaction temperature is 0 ° C to 80 ° C, preferably from 20 ° C to 50 ° C.
- the reaction time is generally 2 to 12 hours, depending on the composition of the mixture and the selected temperature range.
- the preparation of the compounds of the formula 16a, 16b and 16c or mixtures thereof is analogous to the conditions mentioned for the compound of formula 16.
- the compound of formula 17 (not part of the invention) can be prepared, for example, by reacting the compound of formula 16 with dimethylamine in a suitable solvent such as methanol, ethanol, 2-propanol, toluene, THF, methyl THF or dimethoxyethane.
- a suitable solvent such as methanol, ethanol, 2-propanol, toluene, THF, methyl THF or dimethoxyethane.
- the reaction temperature is 60 ° C to 140 ° C, preferably from 80 ° C to 120 ° C.
- the reaction time is generally 4 to 24 hours, depending on the composition of the mixture and the selected temperature range.
- the resulting compound of formula 17 is then crystallized from the reaction mixture with a suitable solvent or solvent mixture, for example methanol, ethanol, 2-propanol, methyl tert-butyl ether or diisopropyl ether.
- the compound of formula 17 can be prepared, for example, by reacting the compound of formula 31 with a suitable reducing agent such as hydrogen / palladium on charcoal in a suitable solvent such as methanol, ethanol, 2-propanol, dichloromethane, toluene, THF, methyl -THF or dimethoxyethane.
- a suitable solvent such as methanol, ethanol, 2-propanol, dichloromethane, toluene, THF, methyl -THF or dimethoxyethane.
- the reaction temperature is 0 ° C to 80 ° C, preferably from 20 ° C to 50 ° C.
- the reaction time is generally 2 to 12 hours, depending on the composition of the mixture and the selected temperature range.
- the resulting compound of formula 17 is then crystallized from the reaction mixture with a suitable solvent or solvent mixture, for example methanol, ethanol, 2-propanol, methyl tert-butyl ether or diisopropyl
- Compound 17 can be further used as follows for the preparation of the compounds of formula I.
- Compound 17a can be further used as follows to prepare the compound of formula Ia.
- Compound 17b can be further used as follows to prepare the compound of formula Ib.
- Compound 17c can be further used as follows to prepare the compound of formula Ic.
- compound 17 is used to prepare compound 53.
- the reaction mixture is cooled to 50 ° C and treated with 40ml of ethyl acetate.
- the suspension is poured onto a mixture of 180 ml of water and 30 ml of 2N hydrochloric acid.
- the phases are separated and the aqueous phase with ethyl acetate extracted.
- the combined organic phases are dried over sodium sulfate and the solvent is evaporated in vacuo.
- the 2,4-difluoro-3'-nitrobenzophenone of formula 8 is crystallized from the remaining residue with 2-propanol.
- reaction mixture is stirred for a further 15 minutes and the complete reaction is monitored by TLC (hepatan / ethyl acetate 2: 1). After aqueous workup, the aldehyde of formula 13 is crystallized with diisopropyl ether.
- triphosgene 900 mg are dissolved in 10 ml of methylene chloride. To this solution is added dropwise within 20 minutes, a solution of 3.0 g (7.6 mmol) of amine of formula 18a and 3 ml of N-ethylmorpholine in 20 ml of methylene chloride at room temperature. Thereafter, the mixture is stirred for a further 1 hour and then a solution of 3.0 g (7.0 mmol) of aniline of the formula 17 ( US 5,994,391 ), dissolved in 20 ml of methylene chloride, slowly added dropwise .. After another 30 minutes, the reaction finished (DC control). It is twice with ges.
- This disulfate can also be obtained as a major product using twice the amount of sulfur trioxide complex.
- This disulfate can also be obtained as a major product using twice the amount of sulfur trioxide complex.
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Description
Die Erfindung betrifft ein Verfahren zur Herstellung von 1,4-Benzothiepin-1,1-Dioxidderivaten, die mit Benzylresten substituiert sind.The invention relates to a process for the preparation of 1,4-benzothiepine-1,1-dioxide derivatives which are substituted by benzyl radicals.
Es sind bereits 1,4-Benzothiepin-1,1-Dioxidderivate beschrieben worden (
Der Erfindung lag die Aufgabe zugrunde, ein verbessertes Verfahren zur Herstellung von bestimmten entantiomerenreinen 1,4-Benzothiepin-1,1-Dioxidderivaten zur Verfügung zu stellen. Insbesondere sollten die Stereozentren an Position 3, 4 und 5 des Thiepinsystems der Verbindung der Formel I optisch rein aufgebaut bzw. erhalten werden.It was an object of the present invention to provide an improved process for the preparation of certain 1,4-benzothiepine 1,1-dioxide deantiomerically pure derivatives. In particular, the stereocenters at positions 3, 4 and 5 of the thiepine system of the compound of the formula I should be optically pure or obtained.
Die Erfindung betrifft daher ein verbessertes Verfahren zur Herstellung der Verbindungen der Formel I
- R2, R2', R3, R3', R4, R4', R5, R5' unabhängig voneinander H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2 N3, CN, S(O)p-R6, O-S(O)p-R6, (C1-C6)-Alkylen-S(O)p-R6, (C1-C6)-Alkylen-O-S(O)p-R6, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, (C1-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, wobei in den Alkylresten ein, mehrere, oder alle Wasserstoff(e) durch Fluor ersetzt sein können;
Phenyl, -(CH2)-Phenyl, -(CH2)n-Phenyl, O-Phenyl, O-(CH2)m-Phenyl, -(CH2)-O-(CH2)m-Phenyl, wobei der Phenylring ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2; - wobei immer mindestens einer der Reste R2, R2', R3, R3', R4, R4', R5, R5' die Bedeutung -O-(CH2)m-Phenyl oder -(CH2)-O-(CH2)m-Phenyl besitzt, wobei der Phenylring ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2;
- R6 H, OH, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2;
- n 2, 3, 4, 5, 6;
- m 1,2,3,4,5,6;
- p 0, 1, 2;
- R 2 , R 2 ' , R 3 , R 3' , R 4 , R 4 ', R 5, R 5' independently of one another are H, Cl, Br, I, OH, - (CH 2 ) -OH, CF 3 , NO 2 N 3 , CN, S (O) p -R6, OS (O) p -R6, (C 1 -C 6 ) alkylene-S (O) p -R6, (C 1 -C 6 ) alkylene-OS (O) p -R6 , COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , (C 1 -C 6 ) -alkyl, ( C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, O- (C 1 -C 6 ) -alkyl, where in the alkyl radicals one, more, or all hydrogen (s) may be replaced by fluorine ;
Phenyl, - (CH 2 ) -phenyl, - (CH 2 ) n -phenyl, O-phenyl, O- (CH 2 ) m -phenyl, - (CH 2 ) -O- (CH 2 ) m -phenyl, wherein the phenyl ring may be substituted one to 3 times by F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O- (C 1 -C 6) alkyl, (C 1 -C 6 ) -Alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) - Alkyl, CONH 2 ; - where at least one of the radicals R 2, R 2 ', R 3, R 3 ', R 4, R 4 ', R 5, R 5' always has the meaning -O- (CH 2 ) m -phenyl or - (CH 2 ) -O- (CH 2 ) m is phenyl, where the phenyl ring can be substituted one to three times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) alkyl, NH 2 , NH (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl, CONH 2 ;
- R 6 is H, OH, (C 1 -C 6 ) -alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 ;
- n 2, 3, 4, 5, 6;
- m 1,2,3,4,5,6;
- p 0, 1, 2;
Die Erfindung betrifft weiterhin verbesserte Verfahren zur Herstellung der Verbindungen der Formeln Ia, Ib und Ic
- R2, R2', R3, R3', R4, R4', R5, R5' unabhängig voneinander H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2 N3, CN, S(O)p-R6, O-S(O)p-R6, (C1-C6)-Alkylen-S(O)p-R6, (C1-C6)-Alkylen-O-S(O)p-R6, COOH, COO(C1-C6)Alkyl, CONH2, CONH(C1-C6)Alkyl, CON[(C1-C6)Alkyl]2, (C1-C6)-Alkyl, (C2-C6)-Alkenyl, (C2-C6)-Alkinyl, O-(C1-C6)-Alkyl, wobei in den Alkylresten ein, mehrere, oder alle Wasserstoff(e) durch Fluor ersetzt sein können;
Phenyl, -(CH2)-Phenyl, -(CH2)n-Phenyl, O-Phenyl, O-(CH2)m-Phenyl, -(CH2)-O-(CH2)m-Phenyl, wobei der Phenylring ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2 CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2; - wobei immer mindestens einer der Reste R2, R2', R3, R3', R4, R4', R5, R5' die Bedeutung -O-(CH2)m-Phenyl oder -(CH2)-O-(CH2)m-Phenyl besitzt, wobei der Phenylring ein bis 3-fach substituiert sein kann mit F, Cl, Br, I, OH, CF3, NO2 CN, OCF3, O-(C1-C6)-Alkyl, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-Alkyl, CONH2;
- R6 H, OH, (C1-C6)-Alkyl, NH2, NH(C1-C6)-Alkyl, N((C1-C6)-Alkyl)2;
- n 2, 3, 4, 5, 6;
- m 1,2,3,4,5,6;
- p 0, 1, 2;
- R 2 , R 2 ' , R 3 , R 3' , R 4 , R 4 ', R 5, R 5' independently of one another are H, Cl, Br, I, OH, - (CH 2 ) -OH, CF 3 , NO 2 N 3 , CN, S (O) p -R6, OS (O) p -R6, (C 1 -C 6 ) alkylene-S (O) p -R6, (C 1 -C 6 ) alkylene-OS (O) p -R6 , COOH, COO (C 1 -C 6 ) alkyl, CONH 2 , CONH (C 1 -C 6 ) alkyl, CON [(C 1 -C 6 ) alkyl] 2 , (C 1 -C 6 ) -alkyl, ( C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl, O- (C 1 -C 6 ) -alkyl, where in the alkyl radicals one, more, or all hydrogen (s) may be replaced by fluorine ;
Phenyl, - (CH 2 ) -phenyl, - (CH 2 ) n -phenyl, O-phenyl, O- (CH 2 ) m -phenyl, - (CH 2 ) -O- (CH 2 ) m -phenyl, wherein the phenyl ring may be monosubstituted to trisubstituted by F, Cl, Br, I, OH, CF 3 , NO 2 CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) Alkyl, NH 2 , NH (C 1 -C 6 ) alkyl, N ((C 1 -C 6 ) alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) -alkyl , CONH 2 ; - where at least one of the radicals R 2, R 2 ', R 3, R 3 ', R 4, R 4 ', R 5, R 5' always has the meaning -O- (CH 2 ) m -phenyl or - (CH 2 ) -O- (CH 2 ) m -phenyl, where the phenyl ring may be substituted one to three times by F, Cl, Br, I, OH, CF 3 , NO 2 CN, OCF 3 , O- (C 1 -C 6 ) -alkyl, ( C 1 -C 6 ) -alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 , SO 2 -CH 3 , COOH, COO- (C 1 -C 6 ) alkyl, CONH 2 ;
- R 6 is H, OH, (C 1 -C 6 ) -alkyl, NH 2 , NH (C 1 -C 6 ) -alkyl, N ((C 1 -C 6 ) -alkyl) 2 ;
- n 2, 3, 4, 5, 6;
- m 1,2,3,4,5,6;
- p 0, 1, 2;
Können Reste oder Substituenten mehrfach in den Verbindungen der Formeln I auftreten, so können sie alle unabhängig voneinander die angegebene Bedeutung haben und gleich oder verschieden sein.If radicals or substituents can occur several times in the compounds of the formulas I, they may all independently of one another have the stated meaning and be identical or to be different.
Die Alkyl-, Alkenyl-, Alkinyl-, Alkylen-, Alkenylen- und Alkinylenreste in den Resten R, R1, R2, R2', R3, R3', R4, R4', R5, R5' und R6 können sowohl geradkettig wie verzweigt sein. Eine Ausführungsform der Erfindung bezieht sich weiterhin auch auf einzelne Reaktionsschritte sowie Zwischenprodukte dieses Verfahrens zur Herstellung der Verbindungen der Formeln 10 und 10a, das folgende Schritte aufweist:
- Die Verbindung der Formel 10 oder 10a lässt sich beispielsweise herstellen indem man die Verbindung der Formel 8 mit einem Thiol der Formel 5 oder 5a, in Gegenwart einer geeigneten Base, wie zum Beispiel Natriumcarbonat, Kaliumcarbonat oderCaesiumcarbonat in einem geeigneten Lösungsmittel wie zum Beispiel Toluol, Dimethylformamid, Dimethylsulfoxid oder N-Methylpyrrolidon umsetzt.
Die erhaltene Verbindung der Formel 10 oder 10a wird anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Toluol, Ethylacetat oder Dichlormethan aus dem Reaktionsgemisch abgetrennt.
- The compound of formula 10 or 10a can be prepared, for example, by reacting the compound of formula 8 with a thiol of formula 5 or 5a in the presence of a suitable base such as sodium carbonate, potassium carbonate or cesium carbonate in a suitable solvent such as toluene, dimethylformamide , Dimethyl sulfoxide or N-methylpyrrolidone.
The resulting compound of formula 10 or 10a is then separated from the reaction mixture by aqueous work-up and extraction with a suitable solvent, for example toluene, ethyl acetate or dichloromethane.
Der Stern an einem Kohlenstoffatom in der Verbindung der Formel 10/10a bedeutet, dass das jeweilige Kohlenstoffatom chiral ist und die Verbindung entweder als R- oder S-Enantiomer oder als Gemisch der beiden Enantiomeren vorliegt.
Bevorzugt wird die Verbindung 10 oder. 10a in enantiomerenreiner Form wie zum Beispiel durch Umsetzung der Verbindung der Formel 8 mit der Verbindung der Formel 5 unter den angegebenen Reaktionsbedingungen hergestellt. Die Herstellung der Verbindung der Formel 10a gelingt analog durch Umsetzung mit der Verbindung der Formel 5a.Preferably, the compound 10 or. 10a in enantiomerically pure form, for example by reacting the compound of formula 8 with the compound of formula 5 under the reaction conditions indicated. The preparation of the compound of formula 10a succeeds analogously by reaction with the compound of formula 5a.
Die Verbindung der Formel 8 lässt sich beispielsweise herstellen indem man die Verbindung der Formel 7 mit 3-Nitrobenzoylchlorid, in Gegenwart eines geeigneten Katalysators, wie zum Beispiel Aluminium-(III)-chlorid, umsetzt.
Die Reaktionstemperatur beträgt dabei von 40 °C bis 140 °C, bevorzugt von 80 °C bis 120 °C. Die Reaktionszeit liegt im allgemeinen bei 2 bis 24 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches.
Die erhaltene Verbindung der Formel 8 wird anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Ethylacetat oder Dichlormethan und anschließende Kristallisation aus dem Reaktionsgemisch abgetrennt.
Die Reaktionstemperatur beträgt dabei von 0 °C bis 100°C, bevorzugt von 0 °C bis 40 °C. Die Reaktionszeit liegt im allgemeinen bei 2 bis 8 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches. Die erhaltene Verbindung der Formel 1 wird anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Ethylacetat oder Dichlormethan aus dem Reaktionsgemisch abgetrennt. Eine Reinigung kann mit Hilfe einer Vakuumdestillation durchgeführt werden. Weiterhin kann die Verbindung der Formel 1 nach den literaturbekannten Verfahren gewonnen werden.
The reaction temperature is from 40 ° C to 140 ° C, preferably from 80 ° C to 120 ° C. The reaction time is generally 2 to 24 hours, depending on the composition of the mixture and the selected temperature range.
The resulting compound of formula 8 is then separated from the reaction mixture by aqueous work-up and extraction with a suitable solvent, for example ethyl acetate or dichloromethane, followed by crystallization.
The reaction temperature is from 0 ° C to 100 ° C, preferably from 0 ° C to 40 ° C. The Reaction time is generally 2 to 8 hours, depending on the composition of the mixture and the selected temperature range. The resulting compound of formula 1 is then separated from the reaction mixture by aqueous work-up and extraction with a suitable solvent, for example ethyl acetate or dichloromethane. A purification can be carried out by means of a vacuum distillation. Furthermore, the compound of formula 1 can be obtained by the literature methods.
Nishii, Sadao. Preparation of 2-ethyl-2-(hydroxymethyl)hexanoic acid. Jpn. Kokai Tokkyo Koho (1989),
Die Verbindung der Formel 2a lässt sich beispielsweise herstellen indem man racemisches 2-butyl-2-ethyl-1,3-propandiol mit chiralen Basen, wie zum Beispiel Chinin, in einem geeigneten Lösungsmittel oder Lösungsmittelgemisch, wie zum Beispiel Toluol, n-Butylacetat oder Aceton/Wasser, umsetzt. Die Reaktionstemperatur der Racematspaltung beträgt dabei 0 °C bis 100°C, bevorzugt von 20 °C bis 60 °C. Die Reaktionszeit liegt im allgemeinen bei 2 bis 24 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches. Die erzielten Enantiomerenüberschüsse (ee) liegen je nach gewählten Bedingungen zwischen 20 und 80% ee. Höhere ee Werte können erzielt werden, wenn die erhaltene Verbindung der Formel 2a anschließend in einem geeigneten Lösungsmittel oder Lösungsmittelgemisch wie zum Beispiel Toluol, n-Butylacetat/Heptan oder Aceton/Wasser umkristallisert wird. Die erzielten Enantiomerenüberschüsse (ee) liegen je nach gewählten Bedingungen zwischen 80 und 99% ee.
Die Verbindung der Formel 2 wird anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Toluol, Ethylacetat oder Dichlormethan aus der Verbindung der Formel 2a gewonnen.
Alternativ kann die Verbindung 2 durch Racematspaltung mit der Verbindung der Formel X2 hergestellt werden. Die Verbindung der Formel 2 wird anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Toluol, Ethylacetat oder Dichlormethan aus der Verbindung der Formel 2b gewonnen.
Das Enantiomer (Formel 2c) der Verbindung 2 kann durch Racematspaltung mit dem Antipoden (Formel X3) der Verbindung X2 hergestellt werden.
Die Verbindungen der Formel 3 und 3a lassen sich beispielsweise herstellen indem man die Verbindung der Formel 2 oder 2c z. B. mit Bromwasserstoffsäure ohne oder mit einem geeigneten Lösungsmittel oder Lösungsmittelgemisch, wie zum Beispiel Toluol, umsetzt. Die Reaktionstemperatur der beträgt dabei 40 °C bis 120°C, bevorzugt von 60 °C bis 100 °C. Die Reaktionszeit liegt im allgemeinen bei 2 bis 24 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches. Die erzielten Ausbeuten liegen je nach gewählten Bedingungen zwischen 60 und 90%.
Die erhaltenen Verbindungen der Formel 3 und 3a bzw. deren Gemisch werden anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Ethylacetat oder Dichlormethan aus dem Reaktionsgemisch abgetrennt. Eine Reinigung kann mit Hilfe einer Vakuumdestillation durchgeführt werden.
Weiterhin können die Verbindungen der Formel 3 und 3a bzw. deren Gemische nach den literaturbekannten Verfahren gewonnen werden.
The resulting compounds of the formula 3 and 3a or their mixture are then separated from the reaction mixture by aqueous workup and extraction with a suitable solvent, for example ethyl acetate or dichloromethane. A purification can be carried out by means of a vacuum distillation.
Furthermore, the compounds of the formula 3 and 3a or mixtures thereof can be obtained by the literature methods.
Mitsuda, Masaru; Oguro, Kazumi; Watabe, Kazuhiko; Hayano, Tetsuji. Preparation of 2-substituted-2-(hydroxymethyl)carboxylic acids (esters) and their intermediates. ; Jpn. Kokai Tokkyo Koho (2006),
Crocq, Veronique; Roussel, Patrick. Process for preparation of new chiral compounds derived from esters of hexanoic acid, and their use in the synthesis of the chiral 2-(bromomethyl)-2-ethylhexanoic acid.;
Alternativ kann die Verbindung der Formel 3 oder 3a direkt aus den Salzen, wie z.B. 2a, 2b und 2d analog den beschriebenen Bedingungen gewonnen werden.
Die Verbindung der Formel 5 lässt sich beispielsweise herstellen indem man das Bromid der Verbindung der Formel 3 z. B. mit Kaliumthioacetat in einem geeigneten Lösungsmittel oder Lösungsmittelgemisch, wie zum Beispiel Toluol oder Aceton umsetzt. Die Reaktionstemperatur der beträgt dabei 0 °C bis 100°C, bevorzugt von 20 °C bis 40 °C. Die Reaktionszeit liegt im allgemeinen bei 2 bis 24 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches. Die erhaltenen Verbindungen der Formel 4 werden anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Ethylacetat oder Dichlormethan aus dem Reaktionsgemisch abgetrennt. Bevorzugterweis wird das Reaktionsprodukt nicht isoliert, sondern direkt in einem geeigneten Lösungsmittel oder Lösungsmittlegemisch, wie z.B. THF/Toluol mit einem Reduktionsmittel wie z. B. Lithiumaluminiumhydrid (LAH) zur Verbindung der Formel 5 reduziert. Die Reaktionstemperatur beträgt dabei 0 °C bis 100°C, bevorzugt 0 °C bis 40 °C. Nach wässriger Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Ethylacetat, Toluol oder Dichlormethan wird das Produkt aus dem Reaktionsgemisch abgetrennt. Eine Reinigung kann mit Hilfe einer Vakuumdestillation durchgeführt werden.
Die Darstellung der Verbindung der Formel 5a gelingt analog.
Eine Ausführungsform der Erfindung bezieht sich weiterhin auch auf einzelne Reaktionsschritte sowie Zwischenprodukte dieses Verfahrens zur Herstellung der Verbindung der Formel 10, das folgende Schritte aufweist:
- Die Verbindung der Formel 10 lässt sich beispielsweise herstellen indem man die Verbindung der Formel 8 mit einem Thiol der Formel 35, in Gegenwart einer geeigneten, wässrigen Base, wie zum Beispiel Natriumcarbonat, Kaliumcarbonat, Caesiumcarbonat, umsetzt.
- The compound of formula 10 can be prepared, for example, by reacting the compound of formula 8 with a thiol of formula 35 in the presence of a suitable aqueous base such as, for example, sodium carbonate, potassium carbonate, cesium carbonate.
Die erhaltene Gemisch der Verbindungen der Formel 30/30a und 10/10a wird durch alkalische Hydrolyse der Verbindung der Formel 30/30a, z.B. mit Natriummethylat in Methanol oder methanolischer Kaliumhydroxid-Lösung, vollständig in die Verbindung der Formel 10/10a überführt und anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Toluol, Ethylacetat oder Dichlormethan aus dem Reaktionsgemisch abgetrennt.
Der Stern an einem Kohlenstoffatom in der Verbindung der Formel 10 bedeutet, dass das jeweilige Kohlenstoffatom chiral ist und die Verbindung entweder als R- oder S-Enantiomer oder als Gemisch der beiden Enantiomeren vorliegt.
Bevorzugt wird die Verbindung 10 oder. 10a in enantiomerenreiner Form wie zum Beispiel durch Umsetzung der Verbindung der Formel 8 mit der Verbindung der Formel 35 unter den angegebenen Reaktionsbedingungen hergestellt. Die Herstellung der Verbindung der Formel 10a gelingt analog durch Umsetzung mit der Verbindung der Formel 5a.Preferably, the compound 10 or. 10a in enantiomerically pure form, for example by reacting the compound of formula 8 with the compound of formula 35 under the reaction conditions indicated. The preparation of the compound of formula 10a succeeds analogously by reaction with the compound of formula 5a.
Die Verbindung der Formel 35 lässt sich beispielsweise herstellen indem man das Bromid der Verbindung der Formel 3 z. B. mit Kaliumthioacetat in einem geeigneten Lösungsmittel oder Lösungsmittelgemisch, wie zum Beispiel Toluol oder Aceton umsetzt. Die Reaktionstemperatur der beträgt dabei 0 °C bis 100°C, bevorzugt von 20 °C bis 40 °C. Die Reaktionszeit liegt im allgemeinen bei 2 bis 24 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches. Die erhaltenen Verbindungen der Formel 4 werden anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Ethylacetat oder Dichlormethan aus dem Reaktionsgemisch abgetrennt. Bevorzugterweis wird das Reaktionsprodukt nicht isoliert, sondern direkt in einem geeigneten Lösungsmittel oder Lösungsmittlegemisch, wie z.B. THF/Toluol mit einem Reduktionsmittel wie z. B. Lithiumaluminiumhydrid zur Verbindung der Formel 5 reduziert. Die Reaktionstemperatur beträgt dabei 0 °C bis 100°C, bevorzugt 0 °C bis 40 °C. Nach wässriger Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Ethylacetat, Toluol oder Dichlormethan wird das Produkt mit einem Säurechlorid oder säureanhydrid unter literaturbekannten Bedingungen umgesetzt. Bevorzugterweise wird das Reaktionsgemisch nach erfolgter Reduktion direkt mit einem Säurehalogenid oder Carbonsäureanhydrid, wie z. B. Acetylchlorid bzw. Acetanhydrid, hydrolysiert und anschließend wässrig aufgearbeitet. Eine Reinigung kann mit Hilfe einer Vakuumdestillation durchgeführt werden.
Eine Ausführungsform der Erfindung bezieht sich weiterhin auch auf einzelne Reaktionsschritte sowie Zwischenprodukte dieses Verfahrens zur Herstellung der Verbindungen der Formel 15, 15a, 15b und 15c, das folgende Schritte aufweist:
- Die Verbindung der Formel 11/11a lässt sich beispielsweise herstellen indem man die Verbindung der Formel 10/10a mit einem geeigneten Reduktionsmittel, wie zum Beispiel Hydrophosphorigesäure/Iod, Natriumborhydrid/Aluminium-(III)-chlorid, Triethylsilan/Trifluoressigsäure, Isobutylaluminiumdichlorid, Butylsilan/Bortrifluorid, Polyhydroxymethylsilan (PHMS) oder Triethylsilan/Bortrifluorid ohne oder in einem geeigneten Lösungsmittel, wie z.B. Toluol, THF, Methyl-THF oder Dimethoxyethan umsetzt. Die Reaktionstemperatur beträgt dabei 20 °C bis 120 °C, bevorzugt von 40 °C bis 80 °C.
Die Herstellung der Verbindung der Formel 11 gelingt analog den für die Verbindungen der Formel 11/11a genannten Bedingungen.
Die Herstellung der Verbindung der Formel 12a gelingt analog den für die Verbindung der Formel 12 genannten Bedingungen.
- The compound of formula 11 / 11a can be prepared, for example, by reacting the compound of formula 10 / 10a with a suitable reducing agent such as, for example, hydrophosphoric acid / iodine, sodium borohydride / aluminum (III) chloride, triethylsilane / trifluoroacetic acid, isobutylaluminum dichloride, butylsilane / Bortrifluorid, polyhydroxymethylsilane (PHMS) or triethylsilane / boron trifluoride without or in a suitable solvent, such as toluene, THF, methyl-THF or dimethoxyethane. The reaction temperature is from 20 ° C to 120 ° C, preferably from 40 ° C to 80 ° C.
The preparation of the compound of formula 11 is possible analogously to the conditions mentioned for the compounds of formula 11 / 11a.
The preparation of the compound of formula 12a succeeds analogously to the conditions mentioned for the compound of formula 12.
Die Reaktionszeit liegt im Allgemeinen bei 1 bis 4 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches. Die erhaltene Verbindunge der Formel 13 wird anschließend durch wässrige Aufarbeitung und Extraktion mit einem geeigneten Lösungsmittel, beispielsweise Toluol, Ethylacetat, Methyl-tert.-butylether oder Dichlormethan aus dem Reaktionsgemisch abgetrennt und kristallisiert.
Die Herstellung der Verbindung der Formel 13a gelingt analog den für die Verbindung der Formel 13 genannten Bedingungen.
The preparation of the compound of formula 13a succeeds analogously to the conditions mentioned for the compound of formula 13.
Die Verbindung der Formel 15 lässt sich beispielsweise herstellen indem man die Verbindung der Formel 13 mit einer geeigneten Base, wie zum Beispiel Kaliumcarbonat, Caesiumcarbonat, DBU, Natrium bzw. Kaliumethylat oder Natrium bzw. Kalium-tert.butylat einem geeigneten Lösungsmittel, wie z.B. 2-Propanol, Toluol, THF, Methyl-THF oder Dimethoxyethan umsetzt. Die Reaktionstemperatur beträgt dabei -70 °C bis 80 °C, bevorzugt von -20 °C bis 25 °C. Das entstandene Isomerengemisch kann anschließend über chromatographische Verfahren, wie z.B. Chromatographie auf Kieselgel und Toluol/Ethylacetat als mobile Phase, oder fraktionierte Kristallisation getrennt werden.
Eine Ausführungsform der Erfindung bezieht sich weiterhin auch auf einzelne Reaktionsschritte sowie Zwischenprodukte desVerfahrens zur Herstellung der Verbindungen der Formeln 17, 17a, 17b und 17c.An embodiment of the invention further relates to individual reaction steps and intermediates of the process for preparing the compounds of the formulas 17, 17a, 17b and 17c.
Die Verbindung der Formel 16 lässt sich beispielsweise herstellen indem man die Verbindung der Formel 15 mit einem geeigneten Reduktionsmittel, wie zum Beispiel Wasserstoff/Palladium auf Aktivkohle in einem geeigneten Lösungsmittel, wie z.B. Methanol, Ethanol, 2-Propanol, Dichlormethan, Toluol, THF, Methyl-THF oder Dimethoxyethan umsetzt. Die Reaktionstemperatur beträgt dabei 0 °C bis 80 °C, bevorzugt von 20 °C bis 50 °C.
Die Reaktionszeit liegt im Allgemeinen bei 2 bis 12 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches.
Die Reaktionszeit liegt im Allgemeinen bei 4 bis 24 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches. Die erhaltene Verbindunge der Formel 17 wird anschließend mit einem geeigneten Lösungsmittel oder Lösungsmittelgemisch, beispielsweise Methanol, Ethanol, 2-Propanol, Methyl-tert.-butylether oder Diisopropylether aus dem Reaktionsgemisch kristallisiert.
The reaction time is generally 2 to 12 hours, depending on the composition of the mixture and the selected temperature range.
The reaction time is generally 4 to 24 hours, depending on the composition of the mixture and the selected temperature range. The resulting compound of formula 17 is then crystallized from the reaction mixture with a suitable solvent or solvent mixture, for example methanol, ethanol, 2-propanol, methyl tert-butyl ether or diisopropyl ether.
Die Herstellung der Verbindungen der Formel 17a, 17b und 17c bzw. deren Gemische gelingt analog den für die Verbindung der Formel 17 genannten Bedingungen.
- Die Verbindung der Formel 31 lässt sich beispielsweise herstellen indem man die Verbindung der Formel 15 mit Dimethylamin in einem geeigneten Lösungsmittel, wie z.B. Methanol, Ethanol, 2-Propanol, Toluol, THF, Methyl-THF oder Dimethoxyethan umsetzt. Die Reaktionstemperatur beträgt dabei 60°C bis 140 °C, bevorzugt von 80 °C bis 120 °C.
- The compound of formula 31 can be prepared, for example, by reacting the compound of formula 15 with dimethylamine in a suitable solvent such as methanol, ethanol, 2-propanol, toluene, THF, methyl-THF or dimethoxyethane. The reaction temperature is 60 ° C to 140 ° C, preferably from 80 ° C to 120 ° C.
Die Herstellung der Verbindungen der Formel 31a, 31b und 31c bzw. deren Gemische gelingt analog den für die Verbindung der Formel 31 genannten Bedingungen.
Die Verbindung der Formel 17 lässt sich beispielsweise herstellen indem man die Verbindung der Formel 31 mit einem geeigneten Reduktionsmittel, wie zum Wasserstoff/Palladium auf Aktivkohle in einem geeigneten Lösungsmittel, wie z.B. Methanol, Ethanol, 2-Propanol, Dichlormethan, Toluol, THF, Methyl-THF oder Dimethoxyethan umsetzt. Die Reaktionstemperatur beträgt dabei 0 °C bis 80 °C, bevorzugt von 20 °C bis 50 °C.
Die Reaktionszeit liegt im Allgemeinen bei 2 bis 12 Stunden, je nach Zusammensetzung des Gemisches und des gewählten Temperaturbereiches. Die erhaltene Verbindunge der Formel 17 wird anschließend mit einem geeigneten Lösungsmittel oder Lösungsmittelgemisch, beispielsweise Methanol, Ethanol, 2-Propanol, Methyl-tert.-butylether oder Diisopropylether aus dem Reaktionsgemisch kristallisiert.
The reaction time is generally 2 to 12 hours, depending on the composition of the mixture and the selected temperature range. The resulting compound of formula 17 is then crystallized from the reaction mixture with a suitable solvent or solvent mixture, for example methanol, ethanol, 2-propanol, methyl tert-butyl ether or diisopropyl ether.
Verbindung 17 kann weiter wie folgt zur Herstellung der Verbindungen der Formel I genutzt werden.
Verbindung 17a kann weiter wie folgt zur Herstellung der Verbindung der Formel Ia genutzt werden.
Verbindung 17b kann weiter wie folgt zur Herstellung der Verbindung der Formel Ib genutzt werden.
Verbindung 17c kann weiter wie folgt zur Herstellung der Verbindung der Formel Ic genutzt werden.
In einer bevorzugten Ausführungsform wird Verbindung 17 zur Herstellung der Verbindung 53 genutzt.
Die Herstellung der Verbindung 53a gelingt z. B. in analoger Form:
Die nachfolgend aufgeführten Beispiele dienen zur Erläuterung der Erfindung, ohne diese jedoch einzuschränken. die in der Tabelle angegebenen Verbindungen können nach dem obigen Verfahren hergestellt werden.
Nachfolgend wird die Herstellung einiger Beispieles detailliert beschrieben, die übrigen Verbindungen der Formel I, Ia, Ib und Ic wurden analog erhalten:The preparation of some examples is described in detail below, the remaining compounds of the formula I, Ia, Ib and Ic were obtained analogously:
35.5g (204mmol) der Carbonsäure der Formel 1 und 63g (194mmol; 0.95äq.) Chinin werden in. 440ml n-Butylacetat und 220ml of n-Heptan suspendiert. Die Mischung wird auf 90°C erhitzt und für 15 Minuten bei dieser Temperatur gerührt. Anschließend wird auf 55°C, dann innerhalb von 12 Stunden auf Raumtemperatur abgekühlt und vom kristallisierten Chininsalz der Formel 1 2a abfiltriert.
Ausbeute: 62g (52%)
ee: 58% (RT: 6 Minuten; Chiralpak AD 250 x 4,6; n-Heptan/Ethanol 25:1; 30°C)35.5 g (204 mmol) of the carboxylic acid of formula 1 and 63 g (194 mmol, 0.95 eq.) Of quinine are dissolved in. 440ml n-butyl acetate and 220ml of n-heptane suspended. The mixture is heated to 90 ° C and stirred for 15 minutes at this temperature. It is then cooled to 55 ° C, then within 12 hours to room temperature and filtered from the crystallized quinine salt of formula 1 2a.
Yield: 62g (52%)
ee: 58% (RT: 6 minutes, Chiralpak AD 250 x 4.6, n-heptane / ethanol 25: 1, 30 ° C)
62g des Chininsalzes der Formel 2a werden in 400ml n-butylacetat und 400ml n-Heptan bei 100 bis 110°C gelöst und langsam über Nacht auf Raumtemperatur abgekühlt. Es wird vom ausgefallenen Feststoff der Formel 2a abgesaugt und im Vakuum getrocknet.
Ausbeute: 43g (70%)
ee: 94% (RT: 6 Minuten; Chiralpak AD 250 x 4,6; n-Heptan/Ethanol 25:1; 30°C)62 g of the quinine salt of formula 2a are dissolved in 400 ml of n-butyl acetate and 400 ml of n-heptane at 100 to 110 ° C and slowly cooled to room temperature overnight. It is filtered off with suction from the precipitated solid of the formula 2a and dried in vacuo.
Yield: 43g (70%)
ee: 94% (RT: 6 minutes, Chiralpak AD 250 x 4.6, n-heptane / ethanol 25: 1, 30 ° C)
26g des Chininsalzes der Formel 2a werden in 110ml 62%iger HBr für 12 Stunden bei 100°C gerührt. Dannach ist die Umsetzung vollständig (DC Ethylacetat/n-Heptan 1:1). Die Lösung wird abgekühlt und mit 100ml Wasser und 100ml Toluol versetzt. Die wässrige Phase abgetrennt und die Toluolphase getrocknet und im Vakuum abdestilliert. Die Carbonsäure der Formel 3 wird über eine Kurzwegdestillation bei 2mbar und 140°C Manteltemperatur gereinigt.
Ausbeute: 11,1g (90%)
1H-NMR (CDCl3): 3,83 (s, 2H); 2,98 (s, 2H); 2,32 (s, 3H); 2,15 (s, 3H); 1,6 - 1,8 (m, 4H); 1,1 - 1,4 (m, 4H); 0,85 (t, 3H); 0,8 (t, 3H)26 g of the quinine salt of formula 2a are stirred in 110 ml of 62% HBr for 12 hours at 100 ° C. Then the reaction is complete (TLC ethyl acetate / n-heptane 1: 1). The solution is cooled and treated with 100 ml of water and 100 ml of toluene. The aqueous phase is separated off and the toluene phase is dried and distilled off in vacuo. The carboxylic acid of formula 3 is purified by short path distillation at 2 mbar and 140 ° C jacket temperature.
Yield: 11.1 g (90%)
1 H-NMR (CDCl3): 3.83 (s, 2H); 2.98 (s, 2H); 2.32 (s, 3H); 2.15 (s, 3H); 1.6-1.8 (m, 4H); 1.1-1.4 (m, 4H); 0.85 (t, 3H); 0.8 (t, 3H)
Alternativverfahrensschritt zu Verbindung 35a mit R gleich Methyl.
64g (0.56mol; 1.12eq.) Kaliumthioacetat werden in 400ml Aceton suspendiert.
118.57g (0.5mol) des Bromides der Formel 3, gelöst in 100ml Aceton warden zugegeben und die Lösung für 4 Stunden bei Raumtemperatur gerührt. Die Suspension wird mit 1500ml Toluol verdünnt und über 100g Silicagel filtriert. Das Filtrat wird bis auf ein Volumen von 1000ml im Vakuum eingeengt, auf 0°C abgekühlt und langsam mit 750ml (0.75mol) einer 1M LAH Lösung in THF versetzt. Die Lösung wird für 1-2 Stunden bei 0°C und über Nacht bei RT gerührt. Die Lösung wird auf 10°C abgekühlt und langsam mit 225ml Acetylchlorid versetzt. Es wird 1 Stunde nachgerührt und anschließend mit 250ml Toluol und 500ml Wasser versetzt. Die Phasen warden separiert und die wässrige Phase noch einmal mit 200ml Toluol extrahiert. Die vereingten Toluolphasen werden über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum abdestilliert. Es wurde die Verbindung der Formel 35a (R gleich Methyl) erhalten.
Ausbeute: 123g (90%)
1H-NMR (CDCl3): 3,83 (s, 2H); 2,98 (s, 2H); 2,32 (s, 3H); 2,15 (s, 3H); 1,6 - 1,8 (m, 4H); 1,1 - 1,4 (m, 4H); 0,85 (t, 3H); 0,8 (t, 3H)64 g (0.56 mol, 1.12 eq.) Of potassium thioacetate are suspended in 400 ml of acetone.
118.57 g (0.5 mol) of the bromide of formula 3 dissolved in 100 ml of acetone were added and the solution stirred for 4 hours at room temperature. The suspension is diluted with 1500 ml of toluene and filtered through 100 g of silica gel. The filtrate is concentrated in vacuo to a volume of 1000 ml, cooled to 0 ° C and slowly treated with 750ml (0.75mol) of a 1M LAH solution in THF. The solution is stirred for 1-2 hours at 0 ° C and overnight at RT. The solution is cooled to 10 ° C and slowly added with 225ml of acetyl chloride. The mixture is stirred for 1 hour and then mixed with 250 ml of toluene and 500 ml of water. The phases were separated and the aqueous phase extracted once more with 200 ml of toluene. The entrained toluene phases are dried over sodium sulfate and the solvent is distilled off in vacuo. There was obtained the compound of formula 35a (R is methyl).
Yield: 123g (90%)
1 H-NMR (CDCl3): 3.83 (s, 2H); 2.98 (s, 2H); 2.32 (s, 3H); 2.15 (s, 3H); 1.6-1.8 (m, 4H); 1.1-1.4 (m, 4H); 0.85 (t, 3H); 0.8 (t, 3H)
64g (0.56mol; 1.12eq.) Kaliumthioacetat werden in 400ml Aceton suspendiert.64 g (0.56 mol, 1.12 eq.) Of potassium thioacetate are suspended in 400 ml of acetone.
118.57g (0.5mol) des Bromides der Formel 3, gelöst in 100ml Aceton wurden zugegeben und die Lösung für 4 Stunden bei Raumtemperatur gerührt. Die Suspension wird mit 1500ml Toluol verdünnt und über 100g Silicagel filtriert. Das Filtrat wird bis auf ein Volumen von 1000ml im Vakuum eingeengt, auf 0°C abgekühlt und langsam mit 750ml (0.75mol) einer 1M LAH Lösung in THF versetzt. Die Lösung wird für 1-2 Stunden bei 0°C und über Nacht bei RT gerührt. Die Lösung wird auf 10°C abgekühlt und langsam mit 700ml 2N Salzsäure versetzt. Es wird 1 Stunde nachgerührt und anschließend mit 250ml Toluol verdünnt. Die Phasen warden separiert und die wässrige Phase noch einmal mit 200ml Toluol extrahiert. Die vereingten Toluolphasen werden über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum abdestilliert. Es wurde die Verbindung der Formel 5 erhalten.
Ausbeute: 103g (90%)
1H-NMR (CDCl3): 3,83 (s, 2H); 2,98 (s, 2H); 1,6 - 1,8 (m, 4H); 1,1 - 1,4 (m, 4H); 0,85 (t, 3H); 0,8 (t, 3H)118.57 g (0.5 mol) of the bromide of the formula 3 dissolved in 100 ml of acetone were added and the solution was stirred for 4 hours at room temperature. The suspension is diluted with 1500 ml of toluene and filtered through 100 g of silica gel. The filtrate is concentrated in vacuo to a volume of 1000 ml, cooled to 0 ° C and slowly treated with 750ml (0.75mol) of a 1M LAH solution in THF. The solution is stirred for 1-2 hours at 0 ° C and overnight at RT. The solution is cooled to 10 ° C and slowly added with 700ml of 2N hydrochloric acid. It is stirred for 1 hour and then diluted with 250 ml of toluene. The phases were separated and the aqueous phase extracted once more with 200 ml of toluene. The entrained toluene phases are dried over sodium sulfate and the solvent is distilled off in vacuo. The compound of the formula 5 was obtained.
Yield: 103g (90%)
1 H-NMR (CDCl3): 3.83 (s, 2H); 2.98 (s, 2H); 1.6-1.8 (m, 4H); 1.1-1.4 (m, 4H); 0.85 (t, 3H); 0.8 (t, 3H)
Zu einer Mischung aus 20g 3-Nitrobenzoylchlorid und 54ml 1,4 -Difluorbenzol werden innerhalb von 30 Minuten bei 20°C Innentemperatur 38,4g wasserfreies Aluminiumchlorid zugegeben, die Temperatur steigt dabei auf 30°C. Die Reaktionsmischung wird für 16 Stunden unter Rückfluß erhitzt. Dannach ist die Reaktion vollständig (DC Kontrolle mit Toluol/AcOEt/CH3CO2H 95:5:3).To a mixture of 20 g of 3-nitrobenzoyl chloride and 54 ml of 1,4-difluorobenzene are added within 30 minutes at 20 ° C internal temperature 38.4 g of anhydrous aluminum chloride, the temperature rises to 30 ° C. The reaction mixture is refluxed for 16 hours. Then the reaction is complete (TLC control with toluene / AcOEt / CH 3 CO 2 H 95: 5: 3).
Die Reaktionsmischung wird im auf 50°C abgekühlt und mit 40ml Essigsäureethylester versetzt. Die Suspension wird auf eine Mischung von 180ml Wasser und 30ml 2N-Salzsäure gegossen. Die Phasen werden getrennt und die wässrige Phase mit Essigsäureethylester nachextrahiert. Die vereingten organischen Phasen werden über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum abgedampft. Das 2,4-Difluoro-3'-nitrobenzophenon der Formel 8 wird aus dem verbleibenden Rückstand mit 2-Propanol kristallisiert.
Ausbeute: 24,6g (86,6%)
1H-NMR (CDCl3): 8,63 (s, 1H); 8,49 (d, 1H); 8,15 (d, 1H); 7,71 (t, 1H); 7,15 - 7,45 (m, 3H)The reaction mixture is cooled to 50 ° C and treated with 40ml of ethyl acetate. The suspension is poured onto a mixture of 180 ml of water and 30 ml of 2N hydrochloric acid. The phases are separated and the aqueous phase with ethyl acetate extracted. The combined organic phases are dried over sodium sulfate and the solvent is evaporated in vacuo. The 2,4-difluoro-3'-nitrobenzophenone of formula 8 is crystallized from the remaining residue with 2-propanol.
Yield: 24.6 g (86.6%)
1 H NMR (CDCl 3): 8.63 (s, 1H); 8.49 (d, 1H); 8.15 (d, 1H); 7.71 (t, 1H); 7.15 - 7.45 (m, 3H)
14,4g (1.15eq.) der Verbindung der Formel 8 und 1.9g Tetrabutylammoniumbromid werden in 80ml Toluol und 70ml einer 2M K2CO3 Lösung gelöst. Die Mischung wird unter Rückfluss erhitzt und innerhalb von 24 Stunden mit 14,5g der Verbindung der Formel 35a, gelöst in 30ml Toluol, versetzt. Die Reaktionsmischung wird noch für weitere 12 Stunden erhitzt. Anschließend wird auf RT abgekühlt, die Phasen getrennt und die organische Phase kurz andestilliert um Restmengen Wasser zu entfernen. Es werden 10ml Methanol und 2,5ml 30%iger Natriummethylat Lösung zugesetzt und 1,5 Stunden gerührt. Anschließend wird die Lösung aufkonzentriert und das Produkt chromatographisch (Eluent: Dichlormethan) gereingt. Es wurde die Verbindung der Formel 10 erhalten.
Ausbeute: 10,1g (57% bezogen auf Verbindung 35a)
1H-NMR (CDCl3): 8,53 (s, 1H); 8,49 (d, 1H); 8,15 (d, 1H); 7,71 (t, 1H); 7,60 -7,68 (m, 1H); 3,45 (d, 2H); 2,83 (s, 2H); 1,05 -1,35 (m, 8H); 0,85 (t, 3H); 0,75 (t, 3H)14.4 g (1.15 eq.) Of the compound of the formula 8 and 1.9 g of tetrabutylammonium bromide are dissolved in 80 ml of toluene and 70 ml of a 2M K 2 CO 3 solution. The mixture is heated to reflux and within 24 hours with 14.5 g of the compound of formula 35a, dissolved in 30 ml of toluene, added. The reaction mixture is heated for a further 12 hours. It is then cooled to RT, the phases are separated and the organic phase is briefly distilled to remove residual amounts of water. 10 ml of methanol and 2.5 ml of 30% sodium methylate solution are added and stirred for 1.5 hours. The solution is then concentrated and the product purified by chromatography (eluent: dichloromethane). The compound of formula 10 was obtained.
Yield: 10.1 g (57% based on compound 35a)
1H-NMR (CDCl3): 8.53 (s, 1H); 8.49 (d, 1H); 8.15 (d, 1H); 7.71 (t, 1H); 7.60-7.68 (m, 1H); 3.45 (d, 2H); 2.83 (s, 2H); 1.05-1.35 (m, 8H); 0.85 (t, 3H); 0.75 (t, 3H)
12,2g (1.15eq.) der Verbindung der Formel 8, 1.6g Tetrabutylammoniumbromid und 2g K2CO3 werden in 120ml Toluol 8 Stunden unter Rückfluss erhitzt. Anschließend wird auf RT abgekühlt, die Phasen getrennt, die Lösung aufkonzentriert und das Produkt chromatographisch (Eluent: Dichlormethan) gereingt. Es wurde die Verbindung der Formel 10 erhalten.
Ausbeute: 6,9 g (46% bezogen auf Verbindung 35a, hellgelbes Öl)
1H-NMR(CDCl3): 8,53 (s, 1H); 8,49 (d, 1H); 8,15 (d, 1H); 7,71 (t, 1H); 7,60 -7,68 (m, 1H); 3,45 (d, 2H); 2,83 (s, 2H); 1,05 - 1,35 (m, 8H); 0,85 (t, 3H); 0,75 (t, 3H)12.2 g (1.15 eq.) Of the compound of the formula 8, 1.6 g of tetrabutylammonium bromide and 2 g of K 2 CO 3 are refluxed in 120 ml of toluene for 8 hours. It is then cooled to RT, the phases are separated, the solution is concentrated and the product purified by chromatography (eluent: dichloromethane). The compound of formula 10 was obtained.
Yield: 6.9 g (46% based on compound 35a, pale yellow oil)
1 H-NMR (CDCl 3 ): 8.53 (s, 1H); 8.49 (d, 1H); 8.15 (d, 1H); 7.71 (t, 1H); 7.60-7.68 (m, 1H); 3.45 (d, 2H); 2.83 (s, 2H); 1.05-1.35 (m, 8H); 0.85 (t, 3H); 0.75 (t, 3H)
11g der Verbindung der Formel 11, 20g Triethylsilan und 25g Bortrifluorid-Diethylether Komplex werden für 8 Stunden bei 65°C Innentemperatur gerührt. Danach ist die Reduktion vollständig (DC: Toluol/Ethylacetat 10:1). Die Reaktionslösung wird auf RT abgekühlt und langsam mit 50ml einer 2M Natriumcarbonat-Lösung versetzt. Anschließend werden 100ml Ethylacetat zugegeben, die organische Phase im Vakuum eingeengt und das Produkt, dieVerbindung der Formel 11, chromatographisch (Eluent: Toluol/Ethylacetat 10:1) gereingt.
Ausbeute: 9,6 g (90,5%, hellgelbes Öl)
Rf = 0.4. C22H28FNO3S (405,54). MS (M + H)+ = 406,5411 g of the compound of formula 11, 20 g of triethylsilane and 25 g of boron trifluoride-diethyl ether complex are stirred for 8 hours at 65 ° C internal temperature. Thereafter, the reduction is complete (TLC: toluene / ethyl acetate 10: 1). The reaction solution is cooled to RT and slowly mixed with 50 ml of a 2M sodium carbonate solution. Then 100 ml of ethyl acetate are added, the organic phase is concentrated in vacuo and the product, the compound of formula 11, purified by chromatography (eluent: toluene / ethyl acetate 10: 1).
Yield: 9.6 g (90.5%, light yellow oil)
Rf = 0.4. C 22 H 28 FNO 3 S (405.54). MS (M + H) + = 406.54
4g Kaliumcarbonat und 12g der Verbindung der Formel 11 werden in 80ml Ethanol, 20ml Acetonitril und 20ml Wasser gelöst. Die Lösung wird auf 5°C abgekühlt und mit 24ml 30%igem H2O2 innerhalb von 1 Stunde versetzt. Die Lösung wird über Nacht gerührt und zur Fällung des Rohproduktes mit 100ml Wasser versetzt. Das Rohprodukt wird abfiltriert, mit Wasser gewaschen und aus Diisopropylether kristallisiert. Die Verbindung der Formel 12 wurde erhalten.
Ausbeute: 11.65g (90%)
1H-NMR (CDCl3): 8,05 - 8,15 (m, 3H); 7,55 -7,65 (m, 2H); 7,08 - 7,15 (m, 1H); 6,90 - 7,00 (m, 1H); 4,60 (s, 2H); 3,60 - 3,75 (m, 2H); 2,95 (s, 2H); 1,05 - 1,45 (m, 8H); 0,85 (t, 3H); 0,75 (t, 3H)4 g of potassium carbonate and 12 g of the compound of formula 11 are dissolved in 80 ml of ethanol, 20 ml of acetonitrile and 20 ml of water. The solution is cooled to 5 ° C and mixed with 24ml 30% H 2 O 2 within 1 hour. The solution is stirred overnight and treated to precipitate the crude product with 100 ml of water. The crude product is filtered off, washed with water and crystallized from diisopropyl ether. The compound of formula 12 was obtained.
Yield: 11.65g (90%)
1H-NMR (CDCl3): 8.05 to 8.15 (m, 3H); 7.55-7.65 (m, 2H); 7.08-7.15 (m, 1H); 6.90 - 7.00 (m, 1H); 4.60 (s, 2H); 3.60-3.75 (m, 2H); 2.95 (s, 2H); 1.05-1.45 (m, 8H); 0.85 (t, 3H); 0.75 (t, 3H)
11.75g (27mol) der Verbindung der Formel 12 und 0.128g (0.022eq.) 4-Acetamido-TEMPO (4-Acetamido-2,2,6,6-tetramethylpiperidin-1-oxyl) werden in 160ml Dichloromethan gelöst. 1.5g of NaBr (0.54eq.) gelöst in 25ml Wasser und 4.45kg (2eq.) NaHCO3, gelöst in 100ml Wasser, werden zugegeben. 20.1g (1.32eq.) einer 12.9%igen NaOCl werden kontinuierlich innerhalb von 2 Stunden zudosiert. Die Reaktionsmischung wird noch 15 Minuten nachgerührt und die vollständige Umsetzung über DC kontrolliert (Hepatan/Ethylacetat 2:1). Nach wässriger Aufarbeitung wird der Aldehyd der Formel 13 mit Diisopropylether kristallisiert.
Ausbeute: 10.5g (90%)
1 H-NMR (400MHz, CDCl3): 9,45 (s, 1H); 8,05 - 8,15 (m, 3H); 7,55 -7,65 (m, 2H); 7,08 - 7,15 (m, 1H); 6,90 - 7,00 (m, 1H); 4,60 (s, 2H); 3,20 (s, 2H); 1,55 - 2,05 (m, 4H); 1,05 - 1,35 (m, 4H);0,85 (t, 3H); 0,75 (t, 3H)11.75 g (27 mol) of the compound of formula 12 and 0.128 g (0.022 eq.) Of 4-acetamido-TEMPO (4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl) are dissolved in 160 ml of dichloromethane. 1.5g of NaBr (0.54eq.) Dissolved in 25ml of water and 4.45kg (2eq.) Of NaHCO 3 dissolved in 100ml of water are added. 20.1 g (1.32 eq.) Of a 12.9% NaOCl are metered in continuously within 2 hours. The reaction mixture is stirred for a further 15 minutes and the complete reaction is monitored by TLC (hepatan / ethyl acetate 2: 1). After aqueous workup, the aldehyde of formula 13 is crystallized with diisopropyl ether.
Yield: 10.5g (90%)
1 H-NMR (400MHz, CDCl3): 9.45 (s, 1H); 8.05-8.15 (m, 3H); 7.55-7.65 (m, 2H); 7.08-7.15 (m, 1H); 6.90 - 7.00 (m, 1H); 4.60 (s, 2H); 3.20 (s, 2H); 1.55 - 2.05 (m, 4H); 1.05-1.35 (m, 4H); 0.85 (t, 3H); 0.75 (t, 3H)
Eine Lösung von 9,3.g (21,4mmol) des Aldehydes der Formel 13 in 80ml THF wird bei 0°C mit 4,1ml (0.18eq.) einer 1M KOtBu in THF versetzt und für 1 Stunde bei dieser Temperatur nachgerührt. Die Reaktionslösung wird mit 0,25g Essigsäure (4,1mmol, 0.18eq.) neutralisiert und im Vakuum eingeengt. Die beiden Isomere (die Verbindungen der Formeln 15 und 15A) werden chromatographisch über Kieselgel getrennt (Eluent: Toluol/Ethylacetat 5:1).A solution of 9.3 g (21.4 mmol) of the aldehyde of formula 13 in 80 ml of THF at 0 ° C with 4.1 ml (0:18eq.) Of 1M KOtBu in THF and stirred for 1 hour at this temperature. The reaction solution is neutralized with 0.25 g of acetic acid (4.1 mmol, 0.18 eq.) And concentrated in vacuo. The two isomers (the compounds of formulas 15 and 15A) are separated by chromatography on silica gel (eluent: toluene / ethyl acetate 5: 1).
Ausbeute Verbindung der Formel 15:4,1g (45%, hellgelber Feststoff)
Rf = 0.38. C22H26FNO5S (435,52). MS (M + H)+ = 436,52
Ausbeute Verbindung der Formel 15A: 3,8g (41%, hellgelber Feststoff)
Rf= 0.49. C22H26FNO5S (435,52). MS (M + H)+ = 436,52 Verbindungen der Formeln 17 und 17A (nicht Teil der Erfindung)Yield compound of formula 15: 4.1 g (45%, light yellow solid)
Rf = 0.38. C 22 H 26 FNO 5 S (435.52). MS (M + H) + = 436.52
Yield Compound of Formula 15A: 3.8g (41%, light yellow solid)
Rf = 0.49. C 22 H 26 FNO 5 S (435.52). MS (M + H) + = 436.52 Compounds of formulas 17 and 17A (not part of the invention)
4g der Verbindung der Formel 15 werden in 40ml Dichlormethan/Ethanol :1 gelöst, mit 400mg Pd/C 5% versetzt und bis zum Ende der Wasserstoffaufnahme (3 - 4 Stunden) bei 3bar hydriert (DC Kontrolle: Ethylacetat/n-Heptan 2:1). Der Katalysator wird abfiltriert und die Lösungsmittel im Vakuum abdestilliert. Es wurde die Verbindung der Formel 16 erhalten.
Ausbeute: 3,7g (98%)
Rf = 0.48. C22H26FNO3S (405,54). MS (M + H)+ = 406,544 g of the compound of formula 15 are dissolved in 40 ml of dichloromethane / ethanol: 1, admixed with 400 mg of Pd / C 5% and hydrogenated until the end of hydrogen uptake (3 - 4 hours) at 3 bar (TLC control: ethyl acetate / n-heptane 2: 1). The catalyst is filtered off and the solvents are distilled off in vacuo. The compound of formula 16 was obtained.
Yield: 3.7g (98%)
Rf = 0.48. C 22 H 26 FNO 3 S (405.54). MS (M + H) + = 406.54
8g der Verbindung 16 werden in einem Druckbehälter vorgelegt und mit 50ml einer 33%igen Lösung von Dimethylamin in Ethanol versetzt. Der Druckbehälter wird Gasdicht verschlossen und die Lösung für mind. 8 Stunden auf 120°C erhitzt. Die Lösung wird abgekühlt und bis zur Kristallsiation langsam mit Wasser versetzt (10ml). Nach erfolgter Kristallisation werden zur vollständigen Fällung noch 50ml Wasser zugesetzt und die Suspension für 1 Stunde gerührt. Das Anilin (Verbindung 17) wird abfiltriert, gut mit Wasser gewaschen und im Vakuum getrocknet.
Ausbeute: 7,8g (91%, farbloser Feststoff)
1H-NMR (400MHz, CDCl3): 7,90 (d, 1H); 7,18 (t, 1H); 6,92 (d, 1H, b); 6,80 (s, 1H, b); 6,63 - 6,67 (m, 1H); 6,45 - 6,53 (m, 1H); 6,10 (s, 1H, b); 5,43 (s, 1H); 4,13 (s, 1H); 3,12 (d, 1H); 2,98 (d, 1H); 2,82 (s, 6H); 2,15 - 2,25 (m, 1H); 1,10 - 1,65 (m, 8H); 0,90 (t, 3H); 0,85 (t, 3H) C24H34N2O3S (437,54). MS (M + H)+ = 438,548 g of the compound 16 are placed in a pressure vessel and mixed with 50 ml of a 33% solution of dimethylamine in ethanol. The pressure vessel is sealed gas-tight and the solution is heated to 120 ° C. for at least 8 hours. The solution is cooled and water is slowly added to the crystallization (10 ml). After crystallization 50 ml of water are added to the complete precipitation and the suspension stirred for 1 hour. The aniline (compound 17) is filtered off, washed well with water and dried in vacuo.
Yield: 7.8 g (91%, colorless solid)
1 H-NMR (400MHz, CDCl 3): 7.90 (d, 1H); 7.18 (t, 1H); 6.92 (d, 1H, b); 6.80 (s, 1H, b); 6.63-6.67 (m, 1H); 6.45-6.53 (m, 1H); 6.10 (s, 1H, b); 5.43 (s, 1H); 4.13 (s, 1H); 3.12 (d, 1H); 2.98 (d, 1H); 2.82 (s, 6H); 2.15-2.25 (m, 1H); 1.10-1.65 (m, 8H); 0.90 (t, 3H); 0.85 (t, 3H) C 24 H 34 N 2 O 3 S (437.54). MS (M + H) + = 438.54
5g der Verbindung 15 werden in einem Druckbehälter vorgelegt und mit 50ml einer 33%igen Lösung von Dimethylamin in Ethanol versetzt. Der Druckbehälter wird Gasdicht verschlossen und die Lösung für mind. 8 Stunden auf 120°C erhitzt. Die Lösungsmittel werden abgedampft und der Rückstand über Kieselgel (Eluent: Ethylacetat/n-Heptan 2:1) chromatographiert.
Ausbeute: 4,76g (90%)
C24H32N2O5S (460,6). MS (M + H)+ = 461,6
Yield: 4.76g (90%)
C 24 H 32 N 2 O 5 S (460.6). MS (M + H) + = 461.6
4g der Verbindung 21 werden in 40ml Ethanol gelöst, mit 400mg Pd/C 5% versetzt und bis zum Ende der Wasserstoffaufnahme (3 - 4 Stunden) bei 3bar hydriert (DC Kontrolle: Ethylacetat/n-Heptan 2:1). Der Katalysator wird abfiltriert und das Filtrat portionsweise, bis zur einsetztenden Kristallisation, mit Wasser versetzt. Es wird noch 30 Minuten nachgerührt und weitere 40ml Wasser nachgegeben. Der farblose Feststoff wird abfiltriert und im Vakuum getrocknet.
Ausbeute der Verbindung 17: 3,8g (91%, farbloser Feststoff)
1H-NMR (400MHz, CDCl3): 7,90 (d, 1H); 7,18 (t, 1H); 6,92 (d, 1H, b); 6,80 (s, 1H, b); 6,63 - 6,67 (m, 1H); 6,45 - 6,53 (m, 1H); 6,10 (s, 1H, b); 5,43 (s, 1H); 4,13 (s, 1H); 3,12 (d, 1H); 2,98 (d, 1H); 2,82 (s, 6H); 2,15 - 2,25 (m, 1H); 1,10 - 1,65 (m, 8H); 0,90 (t, 3H); 0,85 (t, 3H) C24H34N2O3S (437,54). MS (M + H)+ = 438,544 g of compound 21 are dissolved in 40 ml of ethanol, mixed with 400 mg of Pd / C 5% and hydrogenated until the end of hydrogen uptake (3-4 hours) at 3 bar (TLC control: ethyl acetate / n-heptane 2: 1). The catalyst is filtered off and the filtrate is added in portions, until the onset of crystallization, with water. It is stirred for another 30 minutes and added another 40ml of water. The colorless solid is filtered off and dried in vacuo.
Yield of compound 17: 3.8 g (91%, colorless solid)
1 H-NMR (400MHz, CDCl 3): 7.90 (d, 1H); 7.18 (t, 1H); 6.92 (d, 1H, b); 6.80 (s, 1H, b); 6.63-6.67 (m, 1H); 6.45-6.53 (m, 1H); 6.10 (s, 1H, b); 5.43 (s, 1H); 4.13 (s, 1H); 3.12 (d, 1H); 2.98 (d, 1H); 2.82 (s, 6H); 2.15-2.25 (m, 1H); 1.10-1.65 (m, 8H); 0.90 (t, 3H); 0.85 (t, 3H) C 24 H 34 N 2 O 3 S (437.54). MS (M + H) + = 438.54
900 mg Triphosgen werden in 10 ml Methylenchlorid gelöst. Zu dieser Lösung tropft man innerhalb von 20 Minuten eine Lösung aus 3.0 g (7.6 mmol) Amin der Formel 18a und 3 ml N-Ethylmorpholin in 20 ml Methylenchlorid bei Raumtemperatur zu. Danach wird noch 1 Stunde gerührt und dann eine Lösung von 3.0 g (7.0 mmol) Anilin der Formel 17 (
50.0 g (68.9 mmol) Beispiel 52 wird in 500 ml Pyridin gelöst und nach Zugabe von 17 g Pyridin-Sschwefeltrioxid-komplex 30 Minuten bei 60 ° C gerührt. Nach Zugabe von 400 ml Methanol wird am Rotationsverdampfer eingeengt. Der Rückstand wird noch einmal mit 300 ml Methanol abgeraucht und dann mit Flashchromatographie gereinigt. Ausbeute 38.4 g (68 %) der Verbindung der formel Ia als Ammoniumsalz. DC (Methylenchlorid/ Methanol/ konz. Ammoniak 30/5/1). Rf= 0.4. C38H51N3O12S2 x NH3 (823.00). MS (M + H)+ = 804.21. Als Nebenprodukt erhält man 4.0 g (7 %) des Disulfats der Formel 23 als doppeltes Ammoniumsalz. DC (Methylenchlorid/ Methanol/ konz. Ammoniak 30/5/1). Rf= 0.1. C38H50N3O15S3 x 2NH3 (920.09). MS (M + H)+ = 886.45.50.0 g (68.9 mmol) of Example 52 is dissolved in 500 ml of pyridine and stirred for 30 minutes at 60 ° C after addition of 17 g of pyridine-sulfur trioxide complex. After addition of 400 ml of methanol is concentrated on a rotary evaporator. The residue is again smoked with 300 ml of methanol and then purified by flash chromatography. Yield 38.4 g (68%) of the compound of formula Ia as ammonium salt. TLC (methylene chloride / methanol / concentrated ammonia 30/5/1). R f = 0.4. C 38 H 51 N 3 O 12 S 2 x NH 3 (823.00). MS (M + H) + = 804.21. As a by-product, 4.0 g (7%) of the disulfate of the formula 23 are obtained as a double ammonium salt. TLC (methylene chloride / methanol / concentrated ammonia 30/5/1). R f = 0.1. C 38 H 50 N 3 O 15 S 3 x 2 NH 3 (920.09). MS (M + H) + = 886.45.
Dieses Disulfat kann auch als Hauptprodukt erhalten werden, wenn man die doppelte Menge an Schwefeltrioxid-Komplex verwendet.This disulfate can also be obtained as a major product using twice the amount of sulfur trioxide complex.
Die Verbindung 16A wurde analog Verbindung 16 hergestellt.
Ausbeute: 3,7g (98%)
1H-NMR (400MHz, DMSO): 7,95 (m, 1H); 7,25 (t, 1H); 7,10 (t, 1H); 6,72 (d, 1H, b); 6,50 - 6,58 (m, 3H); 5,22 (d, 1H); 5,05 - 5,10 (m, 3H); 3,98 (d, 1H); 3,18 (d, 1H); 3,08 (d, 1H); 2,08 - 2,15 (m, 1H); 1,60 - 1,65 (m, 1H); 1.,05- 1,40 (m, 6H); 0,84 (t, 3H); 0,82 (t, 3H)Compound 16A was prepared analogously to compound 16.
Yield: 3.7g (98%)
1 H NMR (400MHz, DMSO): 7.95 (m, 1H); 7.25 (t, 1H); 7,10 (t, 1H); 6.72 (d, 1H, b); 6.50-6.58 (m, 3H); 5.22 (d, 1H); 5.05 - 5.10 (m, 3H); 3.98 (d, 1H); 3.18 (d, 1H); 3.08 (d, 1H); 2.08 - 2.15 (m, 1H); 1.60 - 1.65 (m, 1H); 1.05- 1.40 (m, 6H); 0.84 (t, 3H); 0.82 (t, 3H)
Die Verbindung 17A wurde analog Verbindung 17 hergestellt.
Ausbeute: 7,6g (88%, farbloser Feststoff)
1H-NMR (400MHz, DMSO): 7,62 (d, 1H); 7,18 (t, 1H); 6,73 (d, 1H, b); 6,50 - 6,58 (m, 2H); 6,48 (d, 1H, b); 6,10 (s, 1H, b); 5,00 - 5,05 (m, 3H); 4,85 (d, 1H); 3,92 (d, 1H); 3,40 -3,50 (m, 1H); 3,00 (d, 1H); 3,03 (d,1H); 2,75 (s, 6H); 2,05 - 2,15 (m, 1H); 1,60 - 1,68 (m, 1H);1,32 - 1,40 (m, 1H); 1,00 - 1,25 (m, 6H);0,85 (t, 3H); 0,80 (t, 3H)Compound 17A was prepared analogously to compound 17.
Yield: 7.6 g (88%, colorless solid)
1 H-NMR (400MHz, DMSO): 7.62 (d, 1H); 7.18 (t, 1H); 6.73 (d, 1H, b); 6.50-6.58 (m, 2H); 6.48 (d, 1H, b); 6.10 (s, 1H, b); 5.00 - 5.05 (m, 3H); 4.85 (d, 1H); 3.92 (d, 1H); 3.40-3.50 (m, 1H); 3.00 (d, 1H); 3.03 (d, 1H); 2.75 (s, 6H); 2.05-2.15 (m, 1H); 1.60-1.68 (m, 1H); 1.32-1.40 (m, 1H); 1.00-1.25 (m, 6H); 0.85 (t, 3H); 0.80 (t, 3H)
2.7 g Triphosgen werden in 30 ml Methylenchlorid gelöst. Zu dieser Lösung tropft man innerhalb von 20 Minuten eine Lösung aus 9.0 g (22.8 mmol) Amin der Formel 18a und 9 ml N-Ethylmorpholin in 60 ml Methylenchlorid bei Raumtemperatur zu. Danach wird noch 1 Stunde gerührt und dann eine Lösung von 9.0 g (21.0 mmol) Anilin der Formel 17a, in 50 ml Methylenchlorid gelöst, langsam zugetropft.. Nach weiteren 30 Minuten ist die Reaktion beendet (DC-Kontrolle). Es wird zweimal mit ges. Natriumchloridlösung gewaschen, über Kieselgel filtriert und eingeengt und man erhält 21 g Rohprodukt der Formel 51 a. Dieses wird in 100 ml Methanol gelöst und mit 5 ml 1 M Natriummethanolat/Methanol Lösung versetzt. Nach 30 Minuten wird die Reaktionslösung mit 10 ml 0.5 M HCL/Methanol Lösung neutrallisiert und eingeengt. Der Rückstand wird mit Flashchromatographie gereinigt. Ausbeute 14 g (92 %) der Verbindung der Formel 52a als farbloser Feststoff. DC (Methylenchlorid/ Methanol/ konz. Ammoniak 30/5/1). Rf= 0.65. C38H51N3O9S (725.91). MS (M + H)+= 726.38.2.7 g of triphosgene are dissolved in 30 ml of methylene chloride. To this solution is added dropwise within 20 minutes, a solution of 9.0 g (22.8 mmol) of amine of formula 18a and 9 ml of N-ethylmorpholine in 60 ml of methylene chloride at room temperature. Thereafter, the mixture is stirred for 1 hour and then a solution of 9.0 g (21.0 mmol) of aniline of the formula 17a, dissolved in 50 ml of methylene chloride, slowly added dropwise .. After a further 30 minutes, the reaction is complete (TLC control). It is twice with ges. Washed sodium chloride solution, filtered through silica gel and concentrated to give 21 g of crude product of formula 51 a. This is dissolved in 100 ml of methanol and treated with 5 ml of 1 M sodium methoxide / methanol solution. After 30 minutes, the reaction solution is neutralized with 10 ml of 0.5 M HCL / methanol solution and concentrated. The residue is purified by flash chromatography. Yield 14 g (92%) of the compound of the formula 52a as a colorless solid. TLC (methylene chloride / methanol / concentrated ammonia 30/5/1). R f = 0.65. C 38 H 51 N 3 O 9 S (725.91). MS (M + H) + = 726.38.
10.0 g (13.8 mmol) Beispiel 52a wird in 100 ml Pyridin gelöst und nach Zugabe von 3.5 g Pyridin-Sschwefeltrioxid-komplex 30 Minuten bei 60 ° C gerührt. Nach Zugabe von 100 ml Methanol wird am Rotationsverdampfer eingeengt. Der Rückstand wird noch einmal mit 100 ml Methanol abgeraucht und dann mit Flashchromatographie gereinigt. Ausbeute 7 g (64 %) der Verbindung der Formel 53a als Ammoniumsalz. DC (Methylenchlorid/ Methanol/ konz. Ammoniak 30/5/1). Rf= 0.35. C38H51N3O12S2 x NH3 (823.00). MS (M + H)+= 804.21.10.0 g (13.8 mmol) of Example 52a is dissolved in 100 ml of pyridine and stirred for 30 minutes at 60 ° C after addition of 3.5 g of pyridine-sulfur trioxide complex. After addition of 100 ml of methanol is concentrated on a rotary evaporator. The residue is again smoked with 100 ml of methanol and then purified by flash chromatography. Yield 7 g (64%) of the compound of formula 53a as the ammonium salt. TLC (methylene chloride / methanol / concentrated ammonia 30/5/1). R f = 0.35. C 38 H 51 N 3 O 12 S 2 x NH 3 (823.00). MS (M + H) + = 804.21.
Als Nebenprodukt erhält man 0.8 g (7 %) des Disulfats der Formel 23a als doppeltes Ammoniumsalz. DC (Methylenchlorid/ Methanol/ konz. Ammoniak 30/5/1). Rf= 0.1.
C38H51N3O15S3 x 2NH3 (920.09). MS (M + H)+ = 886.45.As a by-product is obtained 0.8 g (7%) of the disulfate of the formula 23a as a double ammonium salt. TLC (methylene chloride / methanol / concentrated ammonia 30/5/1). R f = 0.1.
C 38 H 51 N 3 O 15 S 3 x 2 NH 3 (920.09). MS (M + H) + = 886.45.
Dieses Disulfat kann auch als Hauptprodukt erhalten werden, wenn man die doppelte Menge an Schwefeltrioxid-Komplex verwendet.This disulfate can also be obtained as a major product using twice the amount of sulfur trioxide complex.
Claims (48)
- A method for the production of the compound of the formula I
R2, R2', R3, R3', R4, R4', R5, R5', independently of one another, are H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2, N3, CN, S(O)p-R6, O-S(O)p-R6, (C1-C6)-alkylene-S(O)p-R6, (C1-C6)-alkylene-O-S(O)p-R6, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, O-(C1-C6)-alkyl, where, in the alkyl radicals, one, more, or all hydrogen(s) can be replaced by fluorine;
phenyl, -(CH2)-phenyl, -(CH2)n-phenyl, O-phenyl, O-(CH2)m-phenyl, -(CH2)-O-(CH2)m-phenyl, where the phenyl ring may be mono- to trisubstituted with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;where always at least one of the radicals R2, R2', R3, R3', R4, R4', R5, R5' has the meaning -O-(CH2)m-phenyl or -(CH2)-O-(CH2)m-phenyl, where the phenyl ring may be mono- to trisubstituted with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2, SO2-CH3, COOH, COO-(C1-C6)-alkyl, CONH2;R6 is H, OH, (C1-C6)-alkyl, NH2, NH(C1-C6)-alkyl, N((C1-C6)-alkyl)2;n is 2, 3, 4, 5, 6;m is 1, 2, 3, 4, 5, 6;p is 0, 1,2;which comprisesG) reacting the compound of the formula 5
H) reacting the compound of the formula 10 in the presence of BF3 and Et3SiH to give a compound of the formula 11
I) reacting the compound of the formula 11 in the presence of H2O2 to give compound 12
J) reacting the compound of the formula 12 in the presence of TEMPO (2,2,6,6-tetramethylpiperidinyloxyl) to give compound 13
K) reacting the compound of the formula 13 in the presence of tBuOK in THF to give compound 15/15A
L) isolating the compound of the formula 15
M) reacting the compound of the formula 15 with the help of H2/Pd-C to give a compound of the formula 16
N) reacting the compound of the formula 16 in the presence of HNMe2 to give a compound of the formula 17/17A
O) isolating the compound of the formula 17
P) reacting the compound 17 with the compound 18, in which the radicals have the meanings given above
Q) reacting the compound of the formula 19, in which the radicals have the meanings given above, to give a compound of the formula 20, in which the radicals have the meanings given above,
R) reacting the compound of the formula 20, in which the radicals have the meanings given above, to give a compound of the formula Ia, in which the radicals have the meanings given above,
- A compound of the formula 2a
- A compound of the formula 4
- A compound of the formula 4a
- A compound of the formula 5
- A compound of the formula 5a
- A racemate of the comopounds of the formula 35/35a
R is (C1-C6)-alkyl. - A compound of the formula 35
R is (C1-C6)-alkyl. - A compound of the formula 35a
R is (C1-C6)-alkyl. - A compound of the formula 8
- A compound of the formula 10
- A compound of the formula 10a
- A compound of the formula 11
- A compound of the formula 11a
- A compound of the formula 12
- A compound of the formula 12a
- A compound of the formula 13
- A compound of the formula 13a
- A compound of the formula 15
- A compound of the formula 15B
- A compound of the formula 15C
- A compound of the formula 16
- A compound of the formula 16B
- A compound of the formula 16C
- A compound of the formula 17B
- A compound of the formula 17C
- A method for the production of the compound of the formula 2a
- The method for the production of the compound of the formula 2a as claimed in claim 27, wherein the solvent or solvent mixture used for the recrystallization is toluene, n-butyl acetate/heptane or acetone/water.
- A method for the production of the compound of the formula 2
- The method for the production of the compound of the formula 2 as claimed in claim 29, wherein the suitable solvent is toluene, ethyl acetate or dichloromethane.
- A method for the production of the compound of the formula 10
reacting the compound of the formula 8 with the compound of the formula 35a in the presence of an aqueous base and then, in a second step,
completely converting the resulting mixture consisting of the compound of formula 30 and the compound of the formula 10 to the compound of formula 10 by alkaline hydrolysis. - The method for the production of the compound of the formula 10 as claimed in claim 31, wherein the aqueous base used is sodium carbonate, potassium carbonate or cesium carbonate.
- A method for the production of the compound of the formula 11
- The method for the production of the compound of the formula 11 as claimed in claim 33, wherein hydrophosphorous acid/iodine, sodium borohydride/aluminium(III) chloride, triethylsilane/trifluoroacetic acid, isobutylaluminum dichloride, butylsilane/boron trifluoride, polyhydroxymethylsilane (PHMS) or triethylsilane/boron trifluoride is used as a suitable reducing agent.
- A method for the production of the compound of the formula 12
- The method for the production of the compound of the formula 12 as claimed in claim 35, wherein sodium perborate, hydrogen peroxide/sodium tungstate, hydrogen peroxide/molybdenum(IV) oxide dichloride, oxones or hydrogen peroxide/acetonitrile/ethanol is used as suitable oxidizing agent.
- The method for the production of the compound of the formula 13
- The method for the production of the compound of the formula 13 as claimed in claim 37, wherein oxayl chloride/DMSO, sulfur trioxide-pyridine complex/DMSO, pyridinium dichromate, periodane or sodium hypochloride/TEMPO is used as oxidizing agent.
- A method for the production of the compounds of the formulae 15 and 15A
- The method for the production of the compounds of the formulae 15 and 15A, as claimed in claim 39, wherein sodium carbonate, potassium carbonate, cesium carbonate, sodium methylate, potassium methylate, sodium ethylate, potassium ethylate, sodium tert-butylate or potassium tert-butylate is used as suitable base.
- A method for the production of the compound of the formula 16
- The method for the production of the compound of the formula 16 as claimed in claim 41, wherein hydrogen/palladium on activated carbon is used as suitable reducing agent.
- A method for the production of the compound of the formula 17
- A method for the production of the compound of the formula 17
- The method for the production of the compound of the formula I as claimed in claim 1, wherein
R2, R2' R3, R3', R4, R4', R5, R5', independently of one another, are H, OH, -(CH2)-OH, (C1-C6)-alkylene-S(O)p-R6, (C1-C6)-alkylene-O-S(O)p-R6, -O-(CH2)m-phenyl, -(CH2)-O-(CH2)m-phenyl,
where always at least one of the radicals R2, R2', R3, R3', R4, R4', R5, R5' has the meaning -O-(CH2)m-phenyl or -(CH2)-O-(CH2)m-phenyl;
R6 is H, OH;
n is 2, 3, 4, 5, 6;
m is 1, 2, 3, 4, 5, 6;
p is 0, 1,2. - The method for the production of the compound of the formula I as claimed in claim 1 or 45, wherein
R2 is H;
R2' is OH;
R3 is -O-CH2-phenyl;
R3' is H;
R4 is H;
R4' is OH;
R5 is -SO3H, -SO3 -NH4 +,
R5' is H; - A method for the production of the compound of the formula I as claimed in claim 1,45 or 46, wherein the compound of the formula I has the structure 53.
- The compound of the formula 51a, 52a, 53a and 23a
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| PL09737876T PL2282991T3 (en) | 2008-05-02 | 2009-04-29 | Method for the production of 1,4-benzothiepin-1,1-dioxide derivatives |
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| DE200810022017 DE102008022017A1 (en) | 2008-05-02 | 2008-05-02 | Preparing 1,4-benzothiepin-1,1-dioxide derivative, comprises e.g. reacting mercaptomethyl-hexanol compound with difluorobenzoyl-azinic acid compound and converting into e.g. benzo(b)thiepin-4-ol compound followed by isolating and purifying |
| DE102009007825 | 2009-02-07 | ||
| DE102009014637 | 2009-03-24 | ||
| PCT/EP2009/003102 WO2009132832A2 (en) | 2008-05-02 | 2009-04-29 | Method for the production of 1,4-benzothiepin-1,1-dioxide derivatives |
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| US (1) | US8461312B2 (en) |
| EP (1) | EP2282991B1 (en) |
| DK (1) | DK2282991T3 (en) |
| ES (1) | ES2666726T3 (en) |
| PL (1) | PL2282991T3 (en) |
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| US20040147774A1 (en) | 2002-12-20 | 2004-07-29 | Aventis Pharma S.A. | Novel chiral compounds derived from hexanoic acid esters, preparation process and intermediates, use in the synthesis of chiral 2-(bromomethyl)-2-ethylhexanoic acid |
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| US8461312B2 (en) | 2013-06-11 |
| ES2666726T3 (en) | 2018-05-07 |
| DK2282991T3 (en) | 2018-05-07 |
| US20110245486A1 (en) | 2011-10-06 |
| WO2009132832A2 (en) | 2009-11-05 |
| EP2282991A2 (en) | 2011-02-16 |
| WO2009132832A3 (en) | 2010-05-06 |
| PL2282991T3 (en) | 2018-07-31 |
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